Stress can have beneficial and maladaptive consequences depending on its type and duration. Stress can affect motor function and the course of neurodegenerative diseases of the motor system, however, this relationship has not been characterized yet. The proposed projects focus on a systematic investigation of the effects of stress and glucocorticoids, the major stress hormones, on motor function and neurodegeneration in Parkinson's disease (PD). The research proposal has three objectives: 1) Do stress and glucocorticoids affect motor performance? This objective is to characterize how stress or glucocorticoids affect skilled and locomotor movements. Glucocorticoid levels of rats will be manipulated and dose-dependent effects determined. It is expected that high levels of stress or glucocorticoids alter motor performance more likely than lower doses and that skilled movement are more susceptible to stress than locomotion. 2) Do glucocorticoids affect the onset and course of PD? This objective is to investigate the role of glucocorticoids in motor function and neurodegeneration in three rat models for PD, an acute and a progressive neurotoxic lesion, and a slow progressive lesion induced by an environmental toxin, used as a pesticide. Glucocorticoid levels will be manipulated and functional abilities assessed accordingly. It is expected that absence of glucocorticoids or chronically elevated levels lead to detrimental effects in the course of PD. 3) Can drug treatments or experience attenuate glucocorticoid-induced behavioral and histological aggravation in PD? This objective is to examine possible therapeutic interventions to protect the motor system and its function from harmful effects induced by elevated glucocorticoid levels. One series of experiments will investigate a pharmacological approach, which reduces glucocorticoid levels. Another series of experiments will assess the influence of environmental enrichment on the pathology of Parkinson's disease. It is expected that both treatments slow the progression of neural degeneration and diminish severity of motor symptoms. These projects will determine (1) the degree to which stress and glucocorticoids can influence motor learning, performance, and anatomy of the motor system, (2) the role of glucocortcoids in the etiology of PD and the progression of neural death and motor symptoms, and (3) which interventions can alter the influence of glucocorticoids on the course of PD. These approaches will provide the opportunity to understand factors involved in the pathology of PD and to develop novel therapeutic strategies for neurodegenerative motor disorders.